Osteogenesis and adipogenesis control in the BMP signaling pathway
Date
2012
Authors
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Publisher
University of Delaware
Abstract
According to NIH around 50% of women over age 50 are affected by Osteoporosis increasing the risk of fractures and injuries. Osteoporotic conditions may arise from either slow bone formation or increased bone resorption or both. Recent studies showed that the bone marrow of osteoporotic patients have increased accumulation of adipocytes. These adipocytes may either migrate into the bone when the bone becomes brittle or stem cells may differentiate into adipocytes instead of osteoblasts. One of the major growth factors that can determine the cell fate of mesenchymal stem cells into adipocytes or osteoblasts is Bone Morphogenetic Protein 2 (BMP2). We recently identified new protein-protein interaction. We identified that Casein Kinase II binds to the BMP2 type IA receptor. There are three potential CK2 binding sites on the receptor and we designed three peptides blocking specifically the interaction of CK2 with one specific binding site on the receptor. We have also synthesized three mutant varieties of the BMPR1a each having a point mutation at each of these CK2 phosphorylation sites. In this study we have deduced a model for osteogenesis mediated by the mutants. In order to investigate the mechanisms of stem cell differentiation by these peptides we identified Endoglin. Endoglin is a co receptor in the BMP signaling pathway and was identified as a marker for cell fate differentiation. Previous studies have shown that low expression of Endoglin is linked with increased osteogenic potential, while high Endoglin expression is linked with high adipogenic potential. Using RT-PCR we found that Endoglin is upregulated during adipogenesis. Additionally overexpression of Endoglin in mesenchymal cells led to increased adipogenesis suggesting that Endoglin itself is not only a marker, but involved in the mechanism of adipogenesis. Endoglin was specifically upregulated in adipocytes of brown fat origin, since the adipocytes expressed PRDM16 which is a known marker for brown fat. These data reveal a new mechanism of adipocyte differentiation and may assist in the development of new therapeutics decreasing the number of adipocytes in the bone marrow and increasing the number of osteoblasts.